This invention relates to novel substituted 3-pyridyl-4-arylpyrroles and their therapeutic and prophylactic uses. Disorders treated and/or prevented using these compounds include inflammatory and AIDS-related disorders.
Inflammatory cytokines such as TNF-xcex1 are produced via the activity of kinases. Such kinases include the Cytokine Suppressive Antiinflammatory Drug-Binding Protein (CSBP)/p38 kinase, a Mitogen-Activated Protein (MAP) kinase family of serine-threonine protein kinases. Inflammatory cytokines play an important role in a number of inflammatory disorders (1), neurodegenerative disorders (10), and AIDS-related disorders (11-14). Although the precise mechanism of kinases such as p38 is unknown, p38 has been implicated in both the production of TNF-xcex1 and the signaling responses associated with the TNF-xcex1 receptor (6).
Arthritis is a prime example of an inflammatory disorder, and is thus the inflammatory disorder focused on most in this section. Arthritis affects millions of people and can strike at any joint in the human body. Its symptoms range from mild pain and inflammation in affected joints, to severe and debilitating pain and inflammation. Although the disorder is associated mainly with aging adults, it is not restricted to adults.
The most common rheumatoid arthritis therapy involves the use of nonsteroidal anti-inflammatory drugs (NSAID""s) to alleviate symptoms.
However, despite the widespread use of NSAID""s, many individuals cannot tolerate the doses necessary to treat the disorder over a prolonged period of time. In addition, NSAID""s merely treat the symptoms of disorder without affecting the underlying cause.
Other drugs such as methotrexate, gold salts, D-penicillamine and prednisone are often used when patients fail to respond to NSAID""s. These drugs also have significant toxicities and their mechanism of action remains unknown. Monoclonal antibodies to TNF-xcex1 and receptor antagonists to interleukin 1xcex2 (IL-1xcex2) have been shown to reduce symptoms of rheumatoid arthritis in small-scale human clinical trials (2).
In addition to protein-based therapies, there are small molecule agents that inhibit the production of these cytokines and have demonstrated activity in animal rheumatoid arthritis models (3). Of these small molecule agents, SB 203580 has proven effective in reducing the production of TNF-xcex1 and IL-1xcex2 in lipopolysaccharide (LPS)-stimulated human monocyte cell lines with IC50 values of 50 to 100 nM (4).
In addition to in vitro testing results, SB 203580 has been shown to inhibit the production of inflammatory cytokines in rats and mice at IC50 values of 15 to 25 mg/kg (5). SB 203580 reduces the production of inflammatory cytokines by inhibiting the activity of CSBP/p38 kinase at an IC50 of 200 nM (6). Due to SB 203580""s oral activity and potency in animal models, researchers have suggested that a compound with such an activity profile has potential as a viable treatment for rheumatoid arthritis (5).
Pyridylpyrroles and their analogs have also been prepared as cytokine inhibitors and glucagon antagonists (7), and specifically as inhibitors of IL-1xcex2, TNF-xcex1 and other cytokines. Arylpyrroles (8) and triarylpyrroles (9) have also been prepared as cytokine inhibitors.
The role of CSBP/p38 has been implicated recently in various neurodegenerative and AIDS-related disorders. With regard to neurodegenerative disorders, p38 has been shown to have a role in determining whether a cell survives or undergoes neuronal programmed cell death or apoptosis (10, 11).
Also related to AIDS, the Kaposi""s sarcoma-associated herpesvirus HHV8 has been shown to encode a G protein-coupled receptor that activates p38. It has been proposed that this activation contributes to tumorigenesis and angiogenesis leading to Kaposi""s sarcoma (12).
Associated with AIDS is the rapid activation of p38 induced by infection of a CCR5+ human T cell line by SIV, suggesting that p38 may play a role in early viral infection (13). Additionally, p38 inhibitors have been shown to block HIV replication in vitro in a manner that may be TNF-xcex1-independent (14).
In general, arthritisxe2x80x94particularly rheumatoid arthritisxe2x80x94and the host of other inflammatory and AIDS-related disorders all take a severe toll on those afflicted. There is a tremendous need for small molecule agents to treat these disorders. To date, however, no such agents have ever been identified and shown to be clinically effective in humans.
This invention provides a compound having the structure: 
or a pharmaceutically acceptable salt thereof, wherein:
(a) R1 is selected from the group consisting of (i) hydrogen, (ii) C1-5alkyl, (iii) substituted or unsubstituted C1-5alkylamino, (iv) N-containing C1-5alkyl heterocycle selected from thiazolidine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, thiazine, pyrrole and imidazole, (v) phenyl, (vi) phenyl independently substituted with one or more of C1-5alkyl, amino, substituted amino, nitro, nitrile and sulfone, and (vii) pyridine;
(b) R2 is selected from the group consisting of (i) hydrogen, (ii) (CH2)3OH, (iii) substituted or unsubstituted C1-5alkyl phenyl, and (iv) N-containing C1-5alkyl heterocycle selected from thiazolidine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, thiazine, pyrrole and imidazole;
(c) R3 is one or more substituents independently selected from the group consisting of hydrogen, halogen, methoxy, nitro, trifluoromethyl, hydroxy, dimethylamino and methylsulfoxide; and
(d) X is either C or N.
This invention also provides a second compound having the structure: 
or a pharmaceutically acceptable salt thereof, wherein:
(a) R1 is selected from the group consisting of (i) hydrogen, (ii) C1-5alkyl, (iii) substituted or unsubstituted C1-5alkylamino, (iv) N-containing C1-5alkyl heterocycle selected from thiazolidine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, thiazine, pyrrole and imidazole, (v) phenyl, (vi) phenyl independently substituted with one or more of C1-5alkyl, amino, substituted amino, nitro, nitrile and sulfone, and (vii) pyridine;
(b) R2 is selected from the group consisting of (i) hydrogen, (ii) (CH2)3OH, (iii) substituted or unsubstituted C1-5alkyl phenyl, and (iv) N-containing C1-5alkyl heterocycle selected from thiazolidine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, thiazine, pyrrole and imidazole;
(c) R4 is a substituted or unsubstituted heterocycle selected from pyridine, pyrimidine, furan or thiophene; and,
(d) X is either C or N.
This invention further provides a pharmaceutical composition comprising one of the instant compounds and a pharmaceutically acceptable carrier.
This invention still further provides a method of treating a subject having a disorder ameliorated by reducing TNF-xcex1 production and/or p38 activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.
Finally, this invention provides a method of preventing an inflammatory response in a subject, comprising administering to the subject a prophylactically effective amount of the instant pharmaceutical composition either preceding or subsequent to an event anticipated to cause the inflammatory response in the subject.
This invention provides novel substituted 3-pyridyl-4-arylpyrroles. These compounds have surprising usefulness in treating disorders ameliorated by a reduction in TNF-xcex1 production and/or p38 activity, and are therefore useful for treating inflammatory disorders such as rheumatoid arthritis, as well as AIDS-related disorders.
Specifically, this invention provides a first compound having the structure: 
or a pharmaceutically acceptable salt thereof, wherein:
(a) R1 is selected from the group consisting of (i) hydrogen, (ii) C1-5alkyl, (iii) substituted or unsubstituted C1-5alkylamino, (iv) N-containing C1-5alkyl heterocycle selected from thiazolidine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, thiazine, pyrrole and imidazole, (v) phenyl, (vi) phenyl independently substituted with one or more of C1-5alkyl, amino, substituted amino, nitro, nitrile and sulfone, and (vii) pyridine;
(b) R2 is selected from the group consisting of (i) hydrogen, (ii) (CH2)3OH, (iii) substituted or unsubstituted C1-5alkyl phenyl, and (iv) N-containing C1-5alkyl heterocycle selected from thiazolidine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, thiazine, pyrrole and imidazole;
(c) R3 is one or more substituents independently selected from the group consisting of hydrogen, halogen, methoxy, nitro, trifluoromethyl, hydroxy, dimethylamino and methylsulfoxide; and
(d) X is either C or N.
In one embodiment of the first compound:
(a) R1 is selected from the group consisting of (i) hydrogen, (ii) C1-5alkyl, (iii) substituted or unsubstituted C1-5alkylamino, (iv) N-containing C1-5alkyl heterocycle selected from piperidine, morpholine and pyrrolidine, and (v) phenyl substituted with a substituent selected from the group consisting of amino, substituted amino, nitro and nitrile;
(b) R2 is selected from the group consisting of hydrogen and (CH2)3phenyl;
(c) R3 is selected from the group consisting of halogen, nitro and trifluoromethyl; and
(d) X is C.
In the preferred embodiment, the first compound is selected from the group of compounds shown in Table 1.
This invention also provides a second compound having the structure: 
or a pharmaceutically acceptable salt thereof, wherein:
(a) R1 is selected from the group consisting of (i) hydrogen, (ii) C1-5alkyl, (iii) substituted or unsubstituted C1-5alkylamino, (iv) N-containing C1-5alkyl heterocycle selected from thiazolidine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, thiazine, pyrrole and imidazole, (v) phenyl, (vi) phenyl independently substituted with one or more of C1-5alkyl, amino, substituted amino, nitro, nitrile and sulfone, and (vii) pyridine;
(b) R2 is selected from the group consisting of (i) hydrogen, (ii) (CH2)3OH, (iii) substituted or unsubstituted C1-5alkyl phenyl, and (iv) N-containing C1-5alkyl heterocycle selected from thiazolidine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, thiazine, pyrrole and imidazole;
(c) R4 is a substituted or unsubstituted heterocycle selected from pyridine, pyrimidine, furan or thiophene; and,
(d) X is either C or N.
In one embodiment of the second compound:
(a) R1 is selected from the group consisting of (i) C1-5alkyl, (ii) substituted or unsubstituted C1-5alkylamino, (iii) substituted or unsubstituted C1-5alkyl heterocyclic amino, (iv) phenyl, and (v) phenyl independently substituted with one or more of amino, substituted amino, nitro or nitrile;
(b) R2 is selected from the group consisting of hydrogen and (CH2)3phenyl; and
(c) X is C.
The instant compounds can be isolated and used as free bases. They can also be isolated and used as pharmaceutically acceptable salts. Examples of such salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, palmoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic and saccharic.
This invention further provides a pharmaceutical composition comprising one of the instant compounds and a pharmaceutically acceptable carrier.
Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like. The typical solid carrier is an inert substance such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. Parenteral carriers include sodium chloride solution, Ringer""s dextrose, dextrose and sodium chloride, lactated Ringer""s and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer""s dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. All carriers can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.
This invention still further provides a method of treating a subject having a disorder ameliorated by reducing TNF-xcex1 production and/or p38 activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.
In one embodiment, the disorder is an inflammatory disorder. In another embodiment, the disorder is an AIDS-related disorder. Examples of disorders treatable by the instant pharmaceutical composition include, without limitation, rheumatoid arthritis, osteoporosis, osteoarthritis, allergic inflammation, periodontal disorder, inflammatory bowel disorder, septic shock, insulin-dependent diabetes mellitus, non-insulin-dependent diabetes, cachexia, pulmonary fibrosis, myasthenia gravis, Crohn""s disease, hepatitis, primary biliary cirrhosis, acute pancreatitis, allograph rejection, glioblastoma, alopecia areta, psoriasis, ischemia, congestive heart failure, restenosis, atherosclerosis, systemic lupus erythematosus, nephritis, Guillain-Barre Syndrome, viral myocarditis, HIV replication, T-cell depletion in HIV infection, cognitive deficits induced by neuronal inflammation, multiple sclerosis, stroke, neuropathic pain, HIV dementia and Alzheimer""s disease. In the preferred embodiment, the disorder is rheumatoid arthritis.
As used herein, the term xe2x80x9csubjectxe2x80x9d includes, without limitation, any animal or artificially modified animal having a disorder ameliorated by reducing TNF-xcex1 production and/or p38 activity in appropriate cells. In the preferred embodiment, the subject is a human.
As used herein, xe2x80x9cappropriate cellsxe2x80x9d include, by way of example, cells which secrete or are capable of secreting TNF-xcex1, and cells wherein p38 has been activated. Specific examples of appropriate cells include, without limitation, monocytes, macrophages, T lymphocytes, fibroblasts, dendritic cells, Langerhans cells, Kuppfer cells and astroglial cells.
Administering the instant pharmaceutical composition can be effected or performed using any of the various methods known to those skilled in the art. The instant compounds can be administered, for example, intravenously, intramuscularly, orally and subcutaneously. In the preferred embodiment, the instant pharmaceutical composition is administered orally. Additionally, administration can comprise giving the subject a plurality of dosages over a suitable period of time. Such administration regimens can be determined according to routine methods.
As used herein, a xe2x80x9ctherapeutically effective dosexe2x80x9d of a pharmaceutical composition is an amount sufficient to stop, reverse or reduce the progression of a disorder. A xe2x80x9cprophylactically effective dosexe2x80x9d of a pharmaceutical composition is an amount sufficient to prevent a disorder, i.e., eliminate, ameliorate and/or delay the disorder""s onset. Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition. The effective dose for administering the pharmaceutical composition to a human, for example, can be determined mathematically from the results of animal studies.
In one embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.05 mg/kg of body weight to about 200 mg/kg of body weight of the instant pharmaceutical composition. In another embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.5 mg/kg of body weight to about 50 mg/kg of body weight. More specifically, in one embodiment, oral doses range from about 0.05 mg/kg to about 100 mg/kg daily. In another embodiment, oral doses range from about 0.05 mg/kg to about 50 mg/kg daily, and in a further embodiment, from about 0.05 mg/kg to about 20 mg/kg daily. In yet another embodiment, infusion doses range from about 1.0 xcexcg/kg/min to about 1.0xc3x97104 xcexcg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from about several minutes to about several days. In a further embodiment, for topical administration, the instant compound can be combined with a pharmaceutical carrier at a drug/carrier ratio of from about 0.001 to about 0.1.
This invention still further provides a method of preventing an inflammatory response in a subject, comprising administering to the subject a prophylactically effective amount of the instant pharmaceutical composition either preceding or subsequent to an event anticipated to cause the inflammatory response in the subject. In the preferred embodiment, the event is an insect sting or an animal bite.
As used herein, the following chemical terms shall have the meanings as set forth in this paragraph: xe2x80x9cindependentlyxe2x80x9d, when in reference to chemical substituents, shall mean that when more than one substituent exists, the substituents may be the same or different; xe2x80x9calkylxe2x80x9d shall mean straight, cyclic and branched-chain alkyl; xe2x80x9calkoxyxe2x80x9d shall mean O-alkyl; xe2x80x9chalogenxe2x80x9d shall mean fluorine, chlorine, bromine or iodine; xe2x80x9cPhxe2x80x9d shall mean phenyl; xe2x80x9cTCAxe2x80x9d shall mean trichloroacetic acid; xe2x80x9cFCSxe2x80x9d shall mean fetal calf serum; and xe2x80x9cRPMIxe2x80x9d shall mean the medium from the Roswell Park Memorial Institute (Sigma cat # R0833).